Background: Instability of the macrolide, high toxicity and water insolubility of epothilone B
derivatives limit their application as clinical injectable drugs. For example, PEGlated epothilone B was
reported to ameliorate its water solubility and stability, and cyclodextrins polymer (CDP) was also used
to drug delivery of epothilones. However, ectogenic polymers may cause lots of potential adverse reactions
because of incompatibility with human body. Glutathione, a water-soluble endogenous tripeptide,
plays an important role in the biological systems and involves multiple cellular functions, which seems
to be a preferred compound for drug delivery. Thus, this paper report here the synthesis and evaluation
of glutathione-epothilone B.
Methods: Derivatization of epothilone B at 3-hydroxyl group and 7-hydroxyl group by coupling with a
lincker, α-iodoacetic acid, generated a epothilone B-iodoacetic acid derivative, which reacted with glutathilone
to give glutathione-epothilone B. The water-solubility of the conjugate was measured. And the
in vitro inhibitory activity to cancer cells and toxicity of the conjugate was evaluated by MTT assay.
The stability of the conjugate in phosphate buffer saline and in human serum was studied, respectively,
to support the results of the in vitro evaluation.
Results: The solubility in water of the conjugate, glutathione-epothilone B, was remarkably improved to
at least 4000 times greater than that of epothilone B. According to the results of the in vitro evaluation,
the conjugate exhibited potent inhibitory activity to human liver cancer cells (HepG2 cells), which was
slightly more potent than the lead compound epothilone B. Meanwhile, the toxicity of the conjugate was
much lower than that of epothilone B. Releasing epothilone B of the conjugate was observed in human
serum, which was completed in about 8 hours. And the conjuate was more stable in the pH 7.4 phosphate
buffer saline. We believed that the introduction of glutathione can not only increase the stability
of epothilone B, but also lead to reduced toxicity.
Conclusion: This paper reported that the successful synthesis of a more stable and water-soluble prodrug
of epothilone B, glutathione-epothilone B, which exhibited better inhibitory activity to human liver
cancer cells (HepG2 cells). Moreover, the reported conjugate showed much lower toxicity to primary
human hepatocyte than epothilone B.